scholarly journals Recent advances in pre-clinical mouse models of COPD

2013 ◽  
Vol 126 (4) ◽  
pp. 253-265 ◽  
Author(s):  
Ross Vlahos ◽  
Steven Bozinovski
Keyword(s):  
Chronic Inflammation ◽  
Cigarette Smoke ◽  
Mouse Models ◽  
Airflow Limitation ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Small Airways ◽  
Obstructive Pulmonary Disease ◽  
New Therapies ◽  
Progression Of Disease

COPD (chronic obstructive pulmonary disease) is a major incurable global health burden and will become the third largest cause of death in the world by 2020. It is currently believed that an exaggerated inflammatory response to inhaled irritants, in particular cigarette smoke, causes progressive airflow limitation. This inflammation, where macrophages, neutrophils and T-cells are prominent, leads to oxidative stress, emphysema, small airways fibrosis and mucus hypersecretion. The mechanisms and mediators that drive the induction and progression of chronic inflammation, emphysema and altered lung function are poorly understood. Current treatments have limited efficacy in inhibiting chronic inflammation, do not reverse the pathology of disease and fail to modify the factors that initiate and drive the long-term progression of disease. Therefore there is a clear need for new therapies that can prevent the induction and progression of COPD. Animal modelling systems that accurately reflect disease pathophysiology continue to be essential to the development of new therapies. The present review highlights some of the mouse models used to define the cellular, molecular and pathological consequences of cigarette smoke exposure and whether they can be used to predict the efficacy of new therapeutics for COPD.

scholarly journals Chronic Cigarette Smoke Exposure Primes NK Cell Activation in a Mouse Model of Chronic Obstructive Pulmonary Disease

2010 ◽  
Vol 184 (8) ◽  
pp. 4460-4469 ◽  
Author(s):  
Gregory T. Motz ◽  
Bryan L. Eppert ◽  
Brian W. Wortham ◽  
Robyn M. Amos-Kroohs ◽  
Jennifer L. Flury ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Mouse Model ◽  
Pulmonary Disease ◽  
Cigarette Smoke ◽  
Cell Activation ◽  
Nk Cell ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease

scholarly journals Pneumocystis murina Infection and Cigarette Smoke Exposure Interact To Cause Increased Organism Burden, Development of Airspace Enlargement, and Pulmonary Inflammation in Mice

2008 ◽  
Vol 76 (8) ◽  
pp. 3481-3490 ◽  
Author(s):  
Paul J. Christensen ◽  
Angela M. Preston ◽  
Tony Ling ◽  
Ming Du ◽  
W. Bradley Fields ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Pulmonary Inflammation ◽  
Airflow Obstruction ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Respiratory Pathogens ◽  
Obstructive Pulmonary Disease ◽  
Immunocompetent Mice

ABSTRACT Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow obstruction and lung destruction with airspace enlargement. In addition to cigarette smoking, respiratory pathogens play a role in pathogenesis, but specific organisms are not always identified. Recent reports demonstrate associations between the detection of Pneumocystis jirovecii DNA in lung specimens or respiratory secretions and the presence of emphysema in COPD patients. Additionally, human immunodeficiency virus-infected individuals who smoke cigarettes develop early emphysema, but a role for P. jirovecii in pathogenesis remains speculative. We developed a new experimental model using immunocompetent mice to test the interaction of cigarette smoke exposure and environmentally acquired Pneumocystis murina infection in vivo. We hypothesized that cigarette smoke and P. murina would interact to cause increases in total lung capacity, airspace enlargement, and pulmonary inflammation. We found that exposure to cigarette smoke significantly increases the lung organism burden of P. murina. Pulmonary infection with P. murina, combined with cigarette smoke exposure, results in changes in pulmonary function and airspace enlargement characteristic of pulmonary emphysema. P. murina and cigarette smoke exposure interact to cause increased lung inflammatory cell accumulation. These findings establish a novel animal model system to explore the role of Pneumocystis species in the pathogenesis of COPD.

Interleukin-6 neutralization alleviates pulmonary inflammation in mice exposed to cigarette smoke and poly(I:C)

2013 ◽  
Vol 125 (10) ◽  
pp. 483-493 ◽  
Author(s):  
Cedric Hubeau ◽  
John E. Kubera ◽  
Katherine Masek-Hammerman ◽  
Cara M. M. Williams
Keyword(s):  
Cigarette Smoke ◽  
Interleukin 6 ◽  
Neutralizing Antibodies ◽  
Pulmonary Inflammation ◽  
Poly I:C ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Chemokine Ligand ◽  
Synthetic Ligand

Increased systemic and pulmonary levels of IL-6 (interleukin-6) are associated with the severity of exacerbations and decline of lung function in patients with COPD (chronic obstructive pulmonary disease). Whether IL-6 is directly involved or plays a bystander role in the pathophysiology of COPD remains unclear. Here we hypothesized that neutralizing circulating levels of IL-6 would modulate episodes of acute pulmonary inflammation following CS (cigarette smoke) exposure and virus-like challenges. For this purpose, we used a model where C57BL/6 mice were exposed to CS twice daily via a nose-only system, and concomitant periodic intranasal challenge with poly(I:C), a synthetic ligand for TLR3 (Toll-like receptor 3) that mimics the encounter with double stranded RNA that is carried by influenza-like viruses. This protocol recapitulates several aspects of acute pulmonary inflammation associated with COPD, including prominent airway neutrophilia, insensitivity to steroid treatment and increased levels of several inflammatory cytokines in BAL (bronchoalveolar lavage) samples. Although IL-6-deficient mice exposed to CS/poly(I:C) developed pulmonary inflammation similar to WT (wild-type) controls, WT mice exposed to CS/poly(I:C) and treated intraperitoneally with IL-6-neutralizing antibodies showed significantly lower blood counts of lymphocytes and monocytes, lower BAL levels of IL-6 and CXCL1 (CXC chemokine ligand 1)/KC (keratinocyte chemoattractant), as well as reduced numbers of BAL neutrophils, lymphocytes and macrophages. Our results thus indicate that the systemic neutralization of IL-6 significantly reduces CS/poly(I:C)-induced pulmonary inflammation, which may be a relevant approach to the treatment of episodes of acute pulmonary inflammation associated with COPD.

Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD: morphological impact of VEGFR-2 inhibition

2006 ◽  
Vol 290 (5) ◽  
pp. L897-L908 ◽  
Author(s):  
John A. Marwick ◽  
Christopher S. Stevenson ◽  
June Giddings ◽  
William MacNee ◽  
Keith Butler ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cigarette Smoke ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Vegf Receptor ◽  
Obstructive Pulmonary Disease ◽  
Signaling Complex ◽  
Rat Lungs

VEGF is fundamental in the development and maintenance of the vasculature. VEGF165 signaling through VEGF receptor (VEGFR)-2/kinase insert domain receptor (KDR) is a highly regulated process involving the formation of a tertiary complex with glypican (GYP)-1 and neuropilin (NRP)-1. Both VEGF and VEGFR-2 expression are reduced in emphysematous lungs; however, the mechanism of regulation of VEGF165 signaling through the VEGFR-2 complex in response to cigarette smoke exposure in vivo, and in smokers with and without chronic obstructive pulmonary disease (COPD), is still unknown. We hypothesized that cigarette smoke exposure disrupts the VEGF165-VEGFR-2 complex, a potential mechanism in the pathogenesis of emphysema. We show that cigarette smoke exposure reduces NRP-1 and GYP-1 as well as VEGF and VEGFR-2 levels in rat lungs and that VEGF, VEGFR-2, GYP-1, and NRP-1 expression in the lungs of both smokers and patients with COPD are also reduced compared with nonsmokers. Moreover, our data suggest that specific inhibition of VEGFR-2 alone with NVP-AAD777 would appear not to result in emphysema in the adult rat lung. As both VEGF165 and VEGFR-2 expression are reduced in emphysematous lungs, decreased GYP-1 and NRP-1 expression may yet further disrupt VEGF165-VEGFR-2 signaling. Whether or not this by itself is critical for inducing endothelial cell apoptosis and decreased vascularization of the lung seen in emphysema patients is still unclear at present. However, targeted therapies to restore VEGF165-VEGFR-2 complex may promote endothelial cell survival and help to ameliorate emphysema.

Pathobiology of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease

2007 ◽  
Vol 87 (3) ◽  
pp. 1047-1082 ◽  
Author(s):  
Toshinori Yoshida ◽  
Rubin M. Tuder
Keyword(s):  
Cigarette Smoke ◽  
Airway Remodeling ◽  
Chronic Obstructive ◽  
Small Airways ◽  
Mucus Production ◽  
Obstructive Pulmonary Disease ◽  
Maintenance Program ◽  
Chronic Obstructive Pulmonary Diseases ◽  
Cytokine Networks ◽  
Airway Responses

Chronic obstructive pulmonary diseases (COPD), comprised of pulmonary emphysema, chronic bronchitis, and structural and inflammatory changes of small airways, is a leading cause of morbidity and mortality in the world. A better understanding of the pathobiology of COPD is critical for the developing of novel therapies, as the majority of patients with the disease have little therapeutic options at the present time. The pathobiology of COPD encompasses multiple injurious processes including inflammation (excessive or inappropriate innate and adaptive immunity), cellular apoptosis, altered cellular and molecular alveolar maintenance program, abnormal cell repair, extracellular matrix destruction (protease and anti-protease imbalance), and oxidative stress (oxidant and antioxidant imbalance). These processes are triggered by urban and rural air pollutants and active and/or passive cigarette smoke and modified by cellular senescence and infection. A series of receptor-mediated signal transduction pathways are activated by reactive oxygen species and tobacco components, resulting in impairment of a variety of cell signaling and cytokine networks, subsequently leading to chronic airway responses with mucus production, airway remodeling, and alveolar destruction. The authors provide an updated insight into the molecular and cellular pathobiology of COPD based on human and/or animal data.

scholarly journals Self-DNA release and STING-dependent sensing drives inflammation to cigarette smoke in mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Mégane Nascimento ◽  
Aurélie Gombault ◽  
Norinne Lacerda-Queiroz ◽  
Corinne Panek ◽  
Florence Savigny ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Type I Interferon ◽  
Critical Role ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Type I ◽  
Obstructive Pulmonary Disease ◽  
Interferon Pathway ◽  
Dna Release

Abstract Cigarette smoke exposure is a leading cause of chronic obstructive pulmonary disease (COPD), a major health issue characterized by airway inflammation with fibrosis and emphysema. Here we demonstrate that acute exposure to cigarette smoke causes respiratory barrier damage with the release of self-dsDNA in mice. This triggers the DNA sensor cGAS (cyclic GMP-AMP synthase) and stimulator of interferon genes (STING), driving type I interferon (IFN I) dependent lung inflammation, which are attenuated in cGAS, STING or type I interferon receptor (IFNAR) deficient mice. Therefore, we demonstrate a critical role of self-dsDNA release and of the cGAS-STING-type I interferon pathway upon cigarette smoke-induced damage, which may lead to therapeutic targets in COPD.

scholarly journals Cigarette smoke exposure alters phosphodiesterases in human structural lung cells

2020 ◽  
Vol 318 (1) ◽  
pp. L59-L64 ◽  
Author(s):  
Haoxiao Zuo ◽  
Alen Faiz ◽  
Maarten van den Berge ◽  
Senani N. H. Rathnayake Mudiyanselage ◽  
Theo Borghuis ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Cyclic Nucleotides ◽  
Complex Mixture ◽  
Inflammatory Cells ◽  
Pde4 Inhibitor ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Pde Inhibition ◽  
Never Smokers

Cigarette smoke (CS), a highly complex mixture containing more than 4,000 compounds, causes aberrant cell responses leading to tissue damage around the airways and alveoli, which underlies various lung diseases. Phosphodiesterases (PDEs) are a family of enzymes that hydrolyze cyclic nucleotides. PDE inhibition induces bronchodilation, reduces the activation and recruitment of inflammatory cells, and the release of various cytokines. Currently, the selective PDE4 inhibitor roflumilast is an approved add-on treatment for patients with severe chronic obstructive pulmonary disease with chronic bronchitis and a history of frequent exacerbations. Additional selective PDE inhibitors are being tested in preclinical and clinical studies. However, the effect of chronic CS exposure on the expression of PDEs is unknown. Using mRNA isolated from nasal and bronchial brushes and lung tissues of never smokers and current smokers, we compared the gene expression of 25 PDE coding genes. Additionally, the expression and distribution of PDE3A and PDE4D in human lung tissues was examined. This study reveals that chronic CS exposure modulates the expression of various PDE members. Thus, CS exposure may change the levels of intracellular cyclic nucleotides and thereby impact the efficiency of PDE-targeted therapies.

Sign in / Sign up

Export Citation Format

Share Document